The article was prepared by staff members of the Division of Animal Welfare, Office for Protection from Research Risks, National Institutes of Health, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville, MD 20892-7507. [The Animal Welfare Division of OPRR was renamed Office of Laboratory Animal Welfare (OLAW) in 2000.]

The Office for Protection from Research Risks (OPRR) of the National
Institutes of Health (NIH) develops, implements, and oversees compliance with
the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory
Animals (Policy) 1. The PHS Policy and the U.S. Department of
Agriculture's (USDA) Animal Welfare Regulations 2, are the two principal
federal documents that set forth requirements for animal care and use by
institutions using animals in research, testing, and education. One of OPRR's
primary functions is to assist institutions in implementing PHS Policy by
responding to policy-related questions 3,4. The following
represent several frequently asked questions from institutions and the OPRR
responses:

1. The Institutional Animal Care and Use Committee (IACUC) at our
institution is uncertain about what criteria to use in determining what
constitutes a "significant change" to an approved research protocol,
so that it can implement the appropriate review mechanism. How should we
interpret the PHS Policy in this regard?

Owing to the great diversity of research performed at assured institutions,
it is not possible for this Office to anticipate all of the changes that
investigators might potentially make to approved protocols and provide an
exhaustive listing of those considered significant. However, institutions have
requested OPRR to evaluate a variety of situations in which the significance of
protocol changes was a primary concern. As a result, we have identified several
kinds of significant changes that may serve as examples to guide the IACUC in
its determinations. They include but are not limited to: changes in the
objectives of a study; proposals to switch from nonsurvival to survival
surgery; changes in the degree of invasiveness of a procedure or discomfort to
an animal; changes in species or in the approximate number of animals used;
changes in personnel involved in animal procedures; and changes in anesthetic
agent(s), the use or withholding of analgesics, and methods of euthanasia.
Additional factors may involve changes in the duration, frequency, or number of
procedures performed on an animal. Based on these considerations, IACUCs should
develop guidelines to follow at their institution and ensure they inform each
principal investigator. It must become institutional policy that no one may
implement changes categorized as significant prior to IACUC review and approval.

2. Our institution purchases antibodies from commercial sources for use
in various PHS-supported studies conducted in its facilities. Does the PHS
Policy require that the commercial source have an Animal Welfare Assurance on
file with the OPRR?

In the case that standard reagent antibodies (e.g. mouse-antihuman)
are produced by a commercial supplier using their own resources and offering
them for general sale, for example, through a catalogue, the institution may
consider the antibodies to be "off-the-shelf" reagents, and the
supplier is not required to file an Assurance with OPRR. If, on the other hand,
a supplier or contractor produces custom antibodies using antigen(s) provided by
or at the request of a principal investigator, the antibodies are considered "customized"
and the vendor or subcontractor must file an Assurance with OPRR.

Usually it is known in advance that someone intends to perform this kind of
work under a PHS grant. In such cases, the applicant must mark the PHS Grant
Application (PHS Form 398) "yes" for vertebrate animal involvement and
include the appropriate Animal Welfare Assurance number(s), verification of
project-specific date of IACUC protocol review, and the identification of all
project performance sites. All animal-related activities supported by the PHS
must be conducted at Assured institutions and must be reviewed and approved by
an IACUC. When both the PHS Grantee and its Contractor hold OPRR-approved
Assurances, some latitude is allowed in determining which IACUC (if not both)
will review the proposal. However, the institution which subcontracts or
subgrants any animal activity retains partial accountability for providing
effective oversight mechanisms to ensure compliance with the PHS Policy. Part
of that responsibility includes ensuring that subgranted/subcontracted
animal-related activities are conducted only at an Assured institution.

3. How extensive must the animal care and use training program be in our
small institution, and at what frequency should it be offered?

Each Assured Institution is responsible for training its staff to meet the
performance requirements cited in paragraph IV.C.1.a.- g. of the PHS Policy, and
guidelines have been developed to assist institutions to meet these objectives 5,6;.
OPRR recognizes research programs vary from one institution to another, and are
relative to the size and nature of the institution, staffing, numbers of species
and individual animals maintained, and the kinds of research conducted.
Therefore, the scope and depth of instructional programs and the frequency at
which they are offered will also vary. At a minimum, however, the Policy
requires institutions to ensure that individuals who use or provide care for
animals are trained and qualified in the appropriate, species-specific housing
methods, husbandry procedures, and handling techniques. The institution must
ensure that research staff members performing experimental manipulation,
including anesthesia and surgery, are qualified through training or experience
to accomplish such procedures humanely and in a scientifically acceptable
fashion. They must also provide training or instruction in research and testing
methods that minimize the number of animals required to obtain valid results and
minimize animal distress. Institutions must also ensure that professional staff
whose work involves hazardous biological, chemical, or physical agents have
training or experience to assess potential dangers and select and oversee the
implementation of appropriate safeguards. Finally, OPRR strongly recommends
that institutions offer their staff access to training leading to certification
in animal technology such as that available from AALAS or a formally designated
academic program. Institutions should also know and ensure compliance with any
initial and continuing education State requirements for the licensing of
veterinary or animal health technicians.

4. In the event that our IACUC reports a serious noncompliance with the
PHS Policy or deviation from the Guide, we understand that the report
must fully explain the circumstances and actions taken to correct the situation.
How soon after the noncompliance or deviation is identified must we submit the
report? How closely is our institution held to meeting its self-imposed
schedule for correction?

The PHS Policy requires institutions report promptly any serious or
continuing noncompliance with the Policy or serious deviation from the
provisions of the Guide. Examples of noncompliance and deviations
include: conducting an animal-related activity without appropriate IACUC review
and approval; the temporary or permanent interruption of an activity involving
animals by the IACUC; and conditions that jeopardize the health or well-being of
an animal. The USDA's Animal Welfare Regulations are more specific, requiring
institutions report such matters to the Animal Plant and Health Inspection
Service (APHIS) and the funding agency if not resolved within 15 business days
of the completion date specified in the IACUC's initial corrective plan and
schedule. The IACUC should use the interval to investigate and develop a
definitive corrective plan and a schedule for implementation. In many cases, it
also provides ample opportunity for total resolution of the problem. One should
note, however, that solution of the problem does not dismiss the institution's
obligation to file a report with OPRR and APHIS. When the IACUC cannot
completely resolve the noncompliance or deviation within the allotted time, the
institution must present a specific and reasonable corrective plan and schedule.
If the situation directly involves animals and threatens their health and
safety, such plans are to contain interim measures, including possible
relocation of the animals at risk. OPRR's acceptance of a plan and schedule is
usually conditioned on notification when the corrective action is complete. It
is recognized that circumstances which are beyond the institution's control may
arise and prevent the scheduled completion of the plan. In such cases, OPRR
will consider requests to extend the schedule if the circumstances are
adequately described and the proposed new deadline is reasonable.

5. Our institution receives funding from PHS and non-PHS sources. Must
we include those programs, projects, and facilities which are not supported by
the PHS in our Assurance of Compliance?

OPRR advises institutions that the maintenance of uniform and consistent
standards is an essential ingredient in the development and implementation of a
quality animal care and use program. Only when an institution can document that
the animal care and use program funded by a non-PHS source is entirely separate
and distinct, physically and programmatically, from PHS-supported activities
will OPRR consider its exclusion from the Institutional Assurance. Unless there
is such total separation, OPRR cannot accept the potential risks presented to
animals involved in PHS-funded research. Institutions should also keep in mind
the public perception that institutions not wishing to conduct portions of their
animal research programs in accordance with the Policy may be applying a double
standard of animal care to the detriment of overall animal health and
well-being.

6. Our institution uses animals as sentinels in the animal disease
surveillance program, in breeding programs, and as donors for blood and blood
products. Since these animals are not used in research per se, is it
necessary to develop protocols for the review and approval of our IACUC?

PHS Policy applicability is not limited to research. It also includes all
activities involving animals including testing and teaching. OPRR has
determined that although animals used as sentinels, breeding stock, chronic
donors of blood and blood products, or for other similar objectives may not be
part of specific research protocols, their use for these purposes contributes
significantly to the institutional research program and constitutes activities
involving animals. Consequently, the IACUC must receive and approve of
protocols and appropriate systems to monitor the use of animals prior to the
commencement of such activities, and should then perform reviews at the
appropriate intervals (IV.C. of the PHS Policy).

7. Could you describe the kind and extent of the employee health program
required by the PHS Policy?

Principal requirements for an institutional occupational health program are
outlined in the Guide for the Care and Use of Laboratory Animals.
Institutional research programs vary regarding the animal species used and the
potential hazards presented by them. The biological, chemical, or physical
agents employed in the course of the research likewise vary. Thus, the
institution must base their health program on an assessment of the risks present
in its particular animal research program, including those in cagewashing and
other support activities. Basic elements of any health program, however, should
provide: a pre-employment medical evaluation and history; immunization against
tetanus; detailed training on how to perform required procedures safely;
instruction in personal hygiene, zoonoses, and precautions for pregnant women
and others at risk; protective clothing and devices; instruction in first aid
procedures appropriate to potential hazards; and access to medical attention for
the treatment of animal bites, scratches, allergies and other job-related
injuries or illnesses. When there is risk of exposure to rabies through the use
of random-source dogs and cats and certain wildlife species, the institution
should offer preexposure immunization, and should regularly schedule tuberculin
testing for all personnel exposed to nonhuman primates. The institution should
have precautions in place and a zoonoses surveillance mechanism established when
work involves exposure to nonhuman primates and species likely to harbor the
causative agents of diseases such as Q fever, tularemia, hantavirus pulmonary
syndrome, and plague. When research involves infectious diseases, such as
hepatitis B, for which there are safe and effective vaccines, the use of
prophylactic immunizations should also be considered. A health program is
required not only for persons having "frequent contact with animals,"
but for all "personnel who work in laboratory animal facilities."
These include not only animal caretakers, technicians, students, volunteers,
investigators, and veterinarians but facilities maintenance engineers,
housekeepers, security, and other staff. OPRR recommends that the foregoing
phrases be interpreted in the context of the potential risks to which the
persons are exposed. For example, those working full time in closed,
pathogen-free rodent colonies where no hazardous agents are employed are at
considerably less risk than individuals exposed for brief periods to nonhuman
primates, random source dogs and cats, or to hazardous biological, chemical, or
physical agents. Each institution's risk assessment and the implementation of
its health program should rely heavily on input from persons knowledgeable in
occupational safety and health, biosafety, and radiation safety, and include
both preventive as well as diagnostic and treatment features.

Received 8/18/95; accepted 9/7/95

References

1. Public Health Service (PHS). Public Health Service Policy on
Humane Care and Use of Laboratory Animals. US Department of Health and Human
Services. (Available from: National Institutes of Health, Office for Protection
from Research Risks, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville,
MD 20892-7507) Washington, DC, 1986.

3. Division of Animal Welfare, Office for Protection from Research
Risks. The Public Health Service Responds to Commonly Asked Questions. ILAR
News33:68-70, 1991.

4. Division of Animal Welfare, Office for Protection from Research
Risks. Frequently Asked Questions about the Public Health Service Policy on Care
and Use of Laboratory Animals. ILAR News35:47-49, 1993.

5.. Education and Training in the Care and Use of Laboratory
Animals: A Guide for Developing Institutional Programs. Committee on
Educational Programs in Laboratory Animal Science, ILAR, Commission on Life
Sciences, National Research Council. Washington: National Academy Press,
Washington, DC, 1991.